Mechanism and Implications of Brown Adipose Tissue Proliferation in Rats and Monkeys Treated with the Thiazolidinedione Darglitazone, a Potent Peroxisome Proliferator-Activated Receptor-γ Agonist

Abstract

Thiazolidinediones represent an established class of insulin sensitizing agents for treating noninsulin-dependent diabetes mellitus. Darglitazone, a thiazolidinedione approximately 200ϫ more potent than ciglitazone, was evaluated in preclinical safety assessment studies using rats (1, 5, and 50 mg/kg/day) and cynomolgus monkeys (50, 75, and 100 mg/kg/day). Darglitazone was a potent adipogenic agent in rats, causing hyperplastic/hypertrophic changes and firmness of white and perirenal, dorsal thoracic (TBAT), and interscapular brown adipose tissue (BAT). Progressive changes in BAT size, morphology, firmness, and fatty acid composition preceded clinical signs of impaired respiration and the subsequent development of a dose-dependent, life-threatening hydrothorax. The characteristics of the pleural effusate were consistent with lymphatic fluid. These adverse effects were ameliorated/reversed upon drug withdrawal and were insulin-dependent since rats rendered totally insulinopenic by streptozotocin pretreatment did not develop TBAT changes or hydrothorax. Although the effects of darglitazone on BAT changes were consistent with enhanced sensitivity to endogenous glucocorticoids, adrenalectomy, and dietary dehydroepiandrosterone administration were without a protective effect. Treated monkeys also developed white and BAT hyperplasia/hypertrophy, peripheral edema, and hydrothorax-related morbidity/mortality. Both species developed reversible, dose-related reductions in red blood cell parameters and follicular atresia. Peripheral and pulmonary edema are purportedly a multifactorial process involving vasodilatation, increased endothelial permeability, and/or plasma volume expansion due to reduced renal sodium excretion. Moreover, profound alterations in TBAT hypertrophy/hyperplasia/firmness may lead to discrete hydrothorax by restricting normal thoracic lymphatic drainage. Similar effects on adipose tissue, hemodilution, and edema (peripheral and pulmonary) were observed clinically with darglitazone and/or several other structurally similar/dissimilar PPAR-␥ agonists.

The PPAR-γ Agonist, Darglitazone, Restores Acute Inflammatory Responses to Cerebral Hypoxia–Ischemia in the Diabeticob/obMouse

“…Only one such study was conducted in diabetic mice, showing a suppression of proinflammatory gene expression and reduction in infarct size (Tureyen et al, 2007). Darglitazone is a TZD that is 20 to 150 times more g-receptor-selective than either rosiglitazone or pioglitazone, and is almost 10 times more orally potent in restoring euglycemia (Aleo et al, 2003;Oakes et al, 2001). Thus, the objectives of the current study were to investigate the effects of darglitazone treatment on H/I insult in the diabetic ob/ob mice with specific attention to the acute inflammatory response(s).…”

Human Adipocyte Fatty Acid-Binding Protein (aP2) Gene Promoter-Driven Reporter Assay Discriminates Nonlipogenic Peroxisome Proliferator-Activated Receptor γ Ligands

“…However, both in pharmacological and clinical use, TZDs increase adiposity and body weight, and elicit clinical side effects including edema, plasma volume expansion, and hemodilution (Aleo et al, 2003;Schöfl and Lü bben, 2003;Yang et al, 2003). These drawbacks stimulate the search for PPAR␥ modulators with modified pharmacological profiles that regulate fatty acids and glucose metabolism with a reduced increase in adiposity, since this undesirable effect may favor the development of obesity, a risk factor often associated with insulin resistance (Oberfield et al, 1999).…”

Marrow Fat and Bone: New Insights from Mice and Humans

“…Tornvig et al first showed that troglitazone increased marrow adiposity in the Apoe -/-strain, but no changes in bone mass were observed in these mice [16]. Darglitazone is 20 times more potent than rosiglitazone and 150 times more potent than pioglitazone [17]. A dose of 10 mg/(kg day) in 8-month-old male mice resulted in a profound decrease in both trabecular and cortical bone [18], but the effect of this TZD on marrow adiposity was not reported.…”